This invention pertains to the field of oncology. In particular, this invention pertains to the discovery of a tumor suppressor gene implicated in the etiology of nevoid basal cell carcinoma syndrome (NBCCS) and various cancers including basal cell carcinomas.
Many cancers are believed to result from a series of genetic alterations leading to progressive disordering of normal cellular growth mechanisms (Nowell (1976) Science 194:23, Foulds (1958) J. Chronic Dis. 8:2). In particular, the deletion or multiplication of copies of whole chromosomes or chromosomal segments, or specific regions of the genome are common (see, e.g., Smith et al. (1991) Breast Cancer Res. Treat. 18: Suppl. 1: 5-14; van de Vijer & Nusse (1991) Biochim. Biophlys. Acta. 1072: 33-50; Sato et al. (1990) Cancer. Res. 50: 7184-7189). In particular, the amplification and deletion of DNA sequences containing proto-oncogenes and tumor-suppressor genes, respectively, are frequently characteristic of tumorigenesis. Dutrillaux et al. (1990) Cancer Genet. Cytogenet. 49: 203-217.
One cancer-related syndrome that appears to have a strong genetic base is the nevoid basal cell carcinoma syndrome (NBCCS). The nevoid basal cell carcinoma syndrome, also known as Gorlin syndrome and the basal cell nevus syndrome, is an autosomal dominant disorder that predisposes to both cancer and developmental defects (Gorlin (1995) Dermatologic Clinics 13: 113-125). Its prevalence has been estimated at 1 per 56,000, and 1-2% of medulloblastomas and 0.5% of basal cell carcinomas (BCCs) are attributable to the syndrome (Springate (1986) J. Pediatr. Surg. 21: 908-910; Evans et al. (1991) British J. Cancer. 64: 959-961). In addition to basal cell carcinomas (BCCs) and medulloblastomas, NBCCS patients are also at an increased risk for ovarian fibromas, meningiomas, fibrosarcomas, rhabdomyosarcomas, cardiac fibromas and ovarian dermoids (Evans et al. (1991) supra., Evans et al. (1993) J. Med. Genet. 30: 460-464; Gorlin (1995) supra.).
Non-neoplastic features, including odontogenic keratocysts (which are more aggressive in the second and third decades of life), pathognomonic dyskeratotic pittina of the hands and feet, and progressive intracranial calcification (usually evident from the second decade) are very common. There is a broad range of skeletal defects (Gorlin (1995) supra.; Shanley et al. (1994) Am. J Med. Genet. 50: 282-290) including rib, vertebral and shoulder anomalies, pectus excavatum, immobile thumbs and polydactyly. Craniofacial and brain abnormalities include cleft palate, characteristic coarse faces, strabismus, dysgenesis of the corpus callosum macrocephaly and frontal bossing (Gorlin (1995) supra.). Generalized overgrowth (Bale et al. (1991) Am. J. Med Genet. 40: 206-210) and acromegalic appearance are common, but growth hormone and IGF1 levels are not elevated.
Implications for the affected individual can be severe, predominantly due to the prolific basal cell carcinomas which can number more than 500 in a lifetime (Shanley et al. (1994) supra). Expression of many features of the syndrome is variable, but the severity tends to breed true within families (Anderson et al. (1967) Am. J. Hum. Genet., 19: 12-22). This variation between families may reflect specific phenotypic effects of different mutations, modifier genes, or environmental factors (sunlight exposure is likely to play a role in the age of onset and incidence of basal cell carcinomas). One third to one half of patients have no affected relatives and are presumed to be the product of new germ cell mutations (Gorlin (1995) supra.). Unilateral and segmental NBCCS are attributed to somatic mutation in one cell of an early embryo (Gutierrez and Mora (1986) J. Am. Acad. Dermatol. 15: 1023-1029).
The NBCCS syndrome was mapped to one or more genes at chromosome 9q22-31 (Gailani et al. (1992) Cell 69: 111-117; Reis et al. (1992) Lancet 339: 617; Farndon et al. (1992) Lancet 339: 581-2). In addition, it has been demonstrated that the same region is deleted in a high percentage of basal cell carcinomas and other tumors related to the disorder (Gailani et al. (1992) supra.) thus suggesting that the NBCCS gene functions as a tumor suppressor. Inactivation of NBCCS gene(s) may be a necessary if not sufficient event for the development of basal cell carcinomas (Shanley et al. (1995) Hum. Mol. Genet. 4: 129-133; Gailani et al. (1996) J. Natl. Canc. Inst. 88: 349-354).
Since the original mapping of the gene in 1992, linkage studies have narrowed the NBCCS region to a 4 cM interval between D9S180 and D9S196 (Goldstein et al. (1994) Am. J. Hum. Genet. 54: 765-773; Wicking et al. (1994) Genomics 22: 505-511). Reported recombination involving an unaffected individual tentatively placed the gene proximal to D9S287 (Farndon et al. (1994) Genomics 23: 486-489). The 9q22 region, however, is very gene rich and appeared to contain at least two tumor suppressor genes. In addition, Harshrnan et al. (1995) Hum. Mol. Genet. 4: 1259-1266, showed that different methods of identifying cDNAs from a genomic region result in a surprisingly different array of candidate genes. Thus, prior to this invention the specific NBCCS gene was unknown.